LKB1 is a serine/threonine kinase located on chromosome 19p13.3. Inherited mutations in LKB1 give[unreadable] rise to Peutz-Jeghers syndrome, a disorder characterized by benign hemartomas of Gl tract and a[unreadable] predisposition to certain cancers, including lung. While acquired mutations in LKB1 are relatively rare in[unreadable] most sporadic tumor types, more than 30% of NSCLC harbor inactivating mutations in LKB1. Recent[unreadable] progress on the function of LKB1 places this gene at the apex of a novel signaling pathway that ultimately[unreadable] serves to inhibit the mammalian Target of Rapamycin (mTOR). Current evidence supports a model in which[unreadable] LKB1 mediates the suppression of mTOR through the sequential activation of AMP regulated kinase[unreadable] (AMPK) and the tumor suppressor TSC2, overriding PIS kinase/AKT survival signaling under conditions of[unreadable] low energy or nutrient deprivation. Data from the literature and preliminary work from our laboratories[unreadable] indicate that cells with compromised LKB1 function are more resistant to effects of microtubule-targeted[unreadable] chemotherapeutic agents. These data have led us to hypothesize that LKB1 may act as a sensor of[unreadable] microtubule integrity, and that LKB1 mediated suppression of mTOR activity may promote apoptosis in[unreadable] response to microtubule-directed agents. LKB1 is also farnesylated at a CAAX motif in the C-terminus and[unreadable] may be a target of farnesyltransferase inhibitors. Thus, LKB1 and its downstream effectors may represent[unreadable] a convergence point between existing agents like the taxanes that interfere with microtubule dynamics and[unreadable] contemporary signal transduction inhibitors such as the mTOR inhibitors and the farnesyltransferase[unreadable] inhibitors.[unreadable] It is our hypothesis that LKB1/AMPK/TSC2 pathway is a frequent target of inactivation in NSCLC and[unreadable] that the integrity of this pathway is a critical determinant of the sensitivity of NSCLC to selected[unreadable] chemotherapeutic agents. The goals of this proposal are to (i) determine the frequency of LKB1/AMPK[unreadable] signaling pathway alterations in NSCLC, (ii) determine the impact of LKB1/AMPK pathway alterations on[unreadable] the response of NSCLC to selected chemotherapeutic agents, and (iii) determine whether[unreadable] LKB1/AMPK/TSC pathway alterations are predictive of clinical response to therapeutic agents in NSCLC[unreadable] patients. A better understanding of the consequences of altered LKB1/AMPK/TSC2 signaling in NSCLC[unreadable] and its role in chemosensitivity will provide novel insight into the mechanism(s) underlying intrinsic drug[unreadable] resistance and may provide a molecular basis for future implementation of "individualized" therapies.